1. Manipulating niche composition limits damage to haematopoietic stem cells during Plasmodium infection.
- Author
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Haltalli MLR, Watcham S, Wilson NK, Eilers K, Lipien A, Ang H, Birch F, Anton SG, Pirillo C, Ruivo N, Vainieri ML, Pospori C, Sinden RE, Luis TC, Langhorne J, Duffy KR, Göttgens B, Blagborough AM, and Lo Celso C
- Subjects
- Animals, Bone Marrow Cells cytology, Bone Marrow Cells metabolism, Bone Marrow Cells physiology, Endothelial Cells cytology, Endothelial Cells metabolism, Endothelial Cells physiology, Gene Expression Profiling methods, Hematopoiesis drug effects, Hematopoiesis genetics, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Humans, Malaria parasitology, Mesenchymal Stem Cells cytology, Mesenchymal Stem Cells metabolism, Mesenchymal Stem Cells physiology, Mice, Inbred C57BL, Mice, Knockout, Osteoblasts cytology, Osteoblasts metabolism, Osteoblasts physiology, Parathyroid Hormone pharmacology, Plasmodium berghei physiology, Reactive Oxygen Species metabolism, Stem Cell Niche genetics, Hematopoiesis physiology, Hematopoietic Stem Cells physiology, Malaria physiopathology, Stem Cell Niche physiology
- Abstract
Severe infections are a major stress on haematopoiesis, where the consequences for haematopoietic stem cells (HSCs) have only recently started to emerge. HSC function critically depends on the integrity of complex bone marrow (BM) niches; however, what role the BM microenvironment plays in mediating the effects of infection on HSCs remains an open question. Here, using a murine model of malaria and combining single-cell RNA sequencing, mathematical modelling, transplantation assays and intravital microscopy, we show that haematopoiesis is reprogrammed upon infection, whereby the HSC compartment turns over substantially faster than at steady-state and HSC function is drastically affected. Interferon is found to affect both haematopoietic and mesenchymal BM cells and we specifically identify a dramatic loss of osteoblasts and alterations in endothelial cell function. Osteo-active parathyroid hormone treatment abolishes infection-triggered HSC proliferation and-coupled with reactive oxygen species quenching-enables partial rescuing of HSC function.
- Published
- 2020
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